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Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages
bearing the cystic fibrosis-relevant F508del-CFTR mutation
#MMPMID28079883
Ferrari E
; Monzani R
; Villella VR
; Esposito S
; Saluzzo F
; Rossin F
; D'Eletto M
; Tosco A
; De Gregorio F
; Izzo V
; Maiuri MC
; Kroemer G
; Raia V
; Maiuri L
Cell Death Dis
2017[Jan]; 8
(1
): e2544
PMID28079883
show ga
Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is
characterized by recurrent bacterial infections and colonization, mainly by
Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused
by mutations in the gene coding for the cystic fibrosis transmembrane conductance
regulator (CFTR) protein, which functions as a chloride channel in epithelial
cells, macrophages, and other cell types. Impaired bacterial handling by
macrophages is a feature of CF airways, although it is still debated how
defective CFTR impairs bacterial killing. Recent evidence indicates that a
defective autophagy in CF macrophages leads to alterations of bacterial clearance
upon infection. Here we use bone marrow-derived macrophages from transgenic mice
to provide the genetic proof that defective CFTR compromises both uptake and
clearance of internalized Pseudomonas aeruginosa. We demonstrate that the
proteostasis regulator cysteamine, which rescues the function of the most common
F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also
repair the defects of CF macrophages, thus restoring both bacterial
internalization and clearance through a process that involves upregulation of the
pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway.
Altogether these results indicate that cysteamine restores the function of
several distinct cell types, including that of macrophages, which might
contribute to its beneficial effects on CF.
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